Normal diploid cells lose their proliferative capacity as they are serially subcultivated. The senescent cells become blocked in the GO/G1 phase of the cell cycle. Our studies focus on hormonal regulation of the G1 progression and entry into S. Four aspects of this control are of current interest to us: (1) The decline in proliferative response to hydrocortisone (HC) as cells senesce. This includes a decrease in the number of receptors/cell and a defect in the translocation of the activated steroid-receptor complex from the cytosol to the nucleus. (2) The characterizatin of a putative growth factor(s) produced by WI-38 cells when they are exposed to HC. (3) The generation of a mitogenic signal in young cells and the presumed failure to generate such a signal in old cells subsequent to the cell surface binding of epidermal growth factor. (4) The expansion of thymidine triphosphate pools in senescent cells without subsequent entry into S. This apparently represents a block near the G1/S border.